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Lookup NU author(s): Dr Ella DennisORCiD, Professor Michael BriggsORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2025 by the authors.Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) are rare, autosomal dominant skeletal dysplasias characterised by disproportionate short stature, joint deformities, and early-onset osteoarthritis. These conditions result from mutations in key cartilage extracellular matrix (ECM) components, including cartilage oligomeric matrix protein (COMP), matrilin-3, and type IX collagen. Although genetically and clinically heterogeneous, PSACH and MED share convergent pathogenic mechanisms. Misfolded mutant ECM proteins are retained within the endoplasmic reticulum (ER) of growth plate chondrocytes, triggering chronic ER stress and impairing chondrocyte proliferation, differentiation, and survival. Moreover, some of the mutant protein is secreted and incorporated into the matrix, leading to altered collagen fibrillogenesis, disrupted proteoglycan distribution, and compromised biomechanical integrity. These alterations extend beyond cartilage, impacting tendons, ligaments, and muscle–tendon junctions, contributing to joint laxity, impaired force transmission, and mild myopathy. This review discusses the structural and functional consequences of ECM disorganisation in PSACH and MED, highlighting its central role in disease progression and emphasising the importance of considering ECM abnormalities when developing therapeutic strategies for rare short stature-associated skeletal disorders.
Author(s): Dennis EP, Briggs MD
Publication type: Review
Publication status: Published
Journal: International Journal of Molecular Sciences
Year: 2025
Volume: 26
Issue: 20
Online publication date: 15/10/2025
Acceptance date: 08/10/2025
ISSN (print): 1661-6596
ISSN (electronic): 1422-0067
Publisher: Multidisciplinary Digital Publishing Institute (MDPI)
URL: https://doi.org/10.3390/ijms262010057
DOI: 10.3390/ijms262010057
PubMed id: 41155349
Data Access Statement: No new data were created or analysed in this study. Data sharing is not applicable to this article
